Polyamine Regulation in Diabetic Breast Cancer Cells

Polyamines (spermine, spermidine, and putrescine) are involved in basic cellular processes such as cell growth, replication, and transcription. They are highly regulated cations that are elevated in cancer. Upregulation of polyamines can thus develop tumors due to hyper‐proliferation of cells as observed in cancers of the colon, skin, prostate and breast. Inhibitors of polyamine pathway could prevent tumor growth as shown in animal models of colon and skin cancer. Intracellular polyamine is regulated by biosynthesis, intestinal uptake and microbial production. Thus inhibitors of synthesis alone have not been very effective as cytotoxic agents but exhibit cytostatic properties. Diabetic conditions further accelerate the growth and metastasis of cancers such as pancreas, breast, liver, and colorectal, however the role of polyamines in such states has not been investigated. We hypothesized that polyamine regulation affects proliferation of breast cancer cells and normal breast epithelial cells in diabetic conditions. Breast cancer cells (MDA‐MB‐231) and normal breast epithelial cells (MCF‐10A) were treated with normal glucose (NG, 5mM) or high glucose (HG, 25 mM) in the presence/absence of polyamine pathway inhibitors. Cells were then treated with polyamine supplements, following depletion with polyamine pathway inhibitors. There was a time dependent increase in cell proliferation with HG from 48–72 hr compared to NG. This was correlated with an increase in polyamines (putrescine, spermidine) though spermine levels were not changed considerably. Simultaneous treatment with an ornithine decarboxylase (polyamine synthesis enzyme) inhibitor, difluoromethylornithine (DFMO) could prevent cell proliferation, restore polyamines, and normalize polyamine catabolic enzymes with high glucose exposure. In conclusion, polyamine regulation is responsible for proliferation of breast cancer cells and normal breast epithelial cells in diabetic states, which can be prevented using inhibitors affecting polyamine levels in cells. Support or Funding Information Funding : Grants from the UNK Undergraduate Research Fellows Program and UNK Research Services Council Seed Grant Equipment : Microplate Reader (Dr. Nuxoll’s lab), Grant from the National Institute for General Medical Science (NIGMS) (5P20GM103427), a component of the National Institutes of Health (NIH)